Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis
Open accessAbstract
Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.
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Assembly of necrosome upon TNFR1 stimulation impinges on two conditions: pharmacological or genetic CASP8 inactivation, and RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by SMAC mimetics.
“In addition, the assembly of the necrosome upon TNFR1 stimulation impinges on two conditions: (1) pharmacological or genetic CASP8 inactivation [478, 479], and (2) RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by exogenously provided SMAC mimetics, ensuring the release of RIPK1 from complex I (see above) [334, 335, 480, 481].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [334]
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References 34 · Cited by 325
Research works printed but not linked: 1
- [34]Cryns VL Bergeron L Zhu H Li H Yuan J Specific cleavage of alpha-fodrin during Fas- and tumor necrosis factor-induced apoptosis is mediated by an interleukin-1beta-converting enzyme/Ced-3 protease distinct from the poly(ADP-ribose) polymerase protease J. Biol. Chem. 1996 271 31277 31282 10.1074/jbc.271.49.31277 8940132 · DOI
- Authors
- Geng, J., Ito, Y., Shi, L., Amin, P., Chu, J., Ouchida, A. T., Mookhtiar, A. K., Zhao, H., Xu, D., Shan, B., Najafov, A., Gao, G., Akira, S., & Yuan, J.
- Affiliations
- Harvard University (US)
- Chinese Academy of Sciences (CN)
- University of Massachusetts Chan Medical School (US)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Corresponding author
- Yuan, Junying
- ORCID
- Venue
- Nature Communications
- Published
- 2017-08-25
- Volume
- 8
- Issue
- 1
- Pages
- 359-359
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5572456
- OpenAlex
- W2746696507
- Cited by
- 325
- References
- 34
- Citations by year
- 2026: 29 · 2025: 41 · 2024: 34 · 2023: 39 · 2022: 35 · 2021: 38 · 2020: 48 · 2019: 35 · 2018: 21 · 2017: 2 · 2012: 2
- FWCI
- 11.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation
- Nakatomi Foundation
- Chinese Academy of Sciences (2014ZX09102001-002)
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Daiichi Sankyo Foundation of Life Science
- National Institutes of Health (4r01ns082257-04)
- Japan Society for the Promotion of Science
- National Institute on Aging (R01AG047231)
- National Institute of Neurological Disorders and Stroke (R01-NS082257, 1R01NS082257)
- Daiichi Sankyo Europe
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Social Sciences › Anthropology › Death, Funerary Practices, and Mourning
- Keywords
- RIPK1, TAK1, necroptosis, TNF signaling, TNFR1, RIPK3, FADD, NF-κB
- MeSH terms
- MAP Kinase Kinase Kinase 7, Animals, Cells, Cultured, Cycloheximide, Phosphorylation, Tumor Necrosis Factor-alpha, NF-kappa B, Cell Death, MAP Kinase Kinase Kinases, Receptors, Tumor Necrosis Factor, Type I, Mice, Receptor-Interacting Protein Serine-Threonine Kinases
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